Download lec.11-426

Metabolism
• S-oxidation to give sulfoxide derivative …..inactive.
• Terminal N demethylation …….is still active
• C7 hydroxylation ……… inactive compound
• Terminal N-oxidation ………..N-oxide derivative is
inactive
General Methods of Analysis:
• An accurately weighed sample is dissolved in acetone or glacial
acetic acid. Mercuric acetate solution is added and the solution
titrated with 0.1 N perchloric acid with methyl orange as indicator.
• Spectrophotometrically.
• HPLC.
Thioxanthene Derivatives
Synthesis
Fluorobutyrophenones
Haloperidol
• It is useful in the management of psychotic reactions, and
hyperactivity.
• It is a drug of choice for Tourett’s syndrome.
• It is metabolized by oxidative N-dealkylation.
• The oxidation products…………………..
Droperidol
• It may be used as an adjunct to anaesthesia or as an
antiemetic.
• It is frequently used in combination with narcotic
analgesic, fentanyl citrate.
Structure Activity Relationship
1.
All potent compounds have 4-fluorophenylgroup, except
anisoperidone which has a methoxy group in the para position f
phenyl ring.
2. Reduction of the carbonyl group to –CHOH, as well as
replacement by oxygen or sulfur decrease neuroleptic potency,
whereas replacement of the ketone by a sulfone result in a loss
of activity.
X=C=O
= CHOH
= O, N, S or SO2
3.
As a rule, lengthening, shortening, or branching of the propylene chain of 4aminobutyrophenones decrease neuroleptic potency.
4.
Considerable variation is possible in the tertiary amino group with retention of
neuroleptic activity. The basic nitrogen could be a part of a six membered ring,
(piperidine, 1,2,3,6-tetrahydropyridyl, or piperazinyl). Replacement of the sixmembered basic heterocycle by larger or smaller or uncyclized amines
diminishes neuroleptic potency.
5.
Neuroleptic potency is generally associated with 4,4-disubstituted piperidines.
Substitution of 2 or 3 positions of piperidines markedly decreases potency. The
decrease in basicity of piperidine nitrogen by amide formation or quaternization
abolishes activity.
6.
High neuroleptic potency among derivatives of 4-piperazinylbutyrophenone requires an aromatic substituent in 4-position of
the piperazine ring.
e.g. Azabuperone